US8829203B2 - 3′,6-substituted indirubins and their biological applications - Google Patents

3′,6-substituted indirubins and their biological applications Download PDF

Info

Publication number
US8829203B2
US8829203B2 US12/737,640 US73764009A US8829203B2 US 8829203 B2 US8829203 B2 US 8829203B2 US 73764009 A US73764009 A US 73764009A US 8829203 B2 US8829203 B2 US 8829203B2
Authority
US
United States
Prior art keywords
gsk
brs
oxime
indirubin
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US12/737,640
Other languages
English (en)
Other versions
US20110136808A1 (en
Inventor
Laurent Meijer
Leandros Skaltsounis
Emmanuel Mikros
Prokopios Magiatis
Carl Johnson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Original Assignee
Centre National de la Recherche Scientifique CNRS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS filed Critical Centre National de la Recherche Scientifique CNRS
Priority to US12/737,640 priority Critical patent/US8829203B2/en
Publication of US20110136808A1 publication Critical patent/US20110136808A1/en
Assigned to CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) reassignment CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MEIJER, LAURENT, MAGIATIS, PROKOPIOS, MIKROS, Emmanuel, SKALTSOUNIS, LEANDROS, JOHNSON, CARL
Application granted granted Critical
Publication of US8829203B2 publication Critical patent/US8829203B2/en
Assigned to NIH-DEITR reassignment NIH-DEITR CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: VANDERBILT UNIVERSITY
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to 3′,6-substituted indirubins with enhanced selectivity towards glycogen synthase kinase-3 (GSK-3). It also relates to their biological applications.
  • GSK-3 stand out as a particularly interesting and well-studied family of serine/threonine kinases.
  • GSK-3 ⁇ GSK-3 forms
  • GSK-3 ⁇ GSK-3 ⁇
  • GSK-3 ⁇ GSK-3 ⁇
  • GSK-3 are implicated in a large diversity of human diseases, including nervous system disorders such as Alzheimer's disease, schizophrenia, bipolar disorder, diabetes, heart hypertrophy, renal diseases, shock and inflammation, cancers, etc. . . .
  • indirubins derivatives of the bis-indole indirubin (collectively referred to as indirubins) appear as a class of original and promising tools and agents. Their moderate selectivity might be an inconvenient when used as a research reagent, but their combined effects on several disease-relevant targets (in particular CDKs and GSK-3) may constitute an advantage for potential therapeutic applications.
  • indirubins 6-bromo-indirubin-3′-oxime (6BIO) 1-3 has been widely used to investigate the physiological role of GSK-3 in various cellular settings and to alter the fate of embryonic stem cells 1 .
  • the choice of the substitution position is thus highly significant since there are two important areas of the molecule that cannot be altered without dramatic decrease of efficacy on kinases.
  • the first one is the pharmacophore consisting of the lactam nitrogen and carbonyl and the heterocyclic nitrogen of the bis-indole core that form the key hydrogen bonding interaction pattern with the active site of the kinase targets.
  • the second is the bromine substitution at position 6 which is the selectivity determinant of 6BIO towards GSK-3 ⁇ .
  • a detailed analysis of the crystal structure of GSK-3 ⁇ in complex with 6BIO was carried out by the inventors. On the basis of the information thus obtained, they considered that the 3′ position was critical for carrying out chemical modifications on the indirubin scaffold.
  • An object of the invention is then to provide new 3′,6-substituted indirubins having enhanced selectivity towards GSK-3.
  • Another object of the invention is to provide a method for obtaining said indirubins.
  • the invention aims to provide pharmaceutical compositions and biological reagents containing said indirubins as active principles as well as a method of treating pathologies associated with GSK-3 deregulations comprising the use of such active principles.
  • the invention also relates to the pharmaceutically acceptable salts of the above defined derivatives.
  • These salts comprise, inter alia, the chlorides, acetates, succinates, citrates of the above disclosed indirubins.
  • R 1 is halogen or OH.
  • R 1 is N (R 2 , R 3 ).
  • R 2 and R 3 are C1-C5 alkyl, optionally substituted by A 1 such as above defined.
  • R 2 and R 3 are part of a pyrrol, morpholinyl, piperazinyl radical, said radical being optionally substituted by one or several A1 and the piperazinyl radical being optionally substituted on the nitrogen at position by a C1-C5 alkyl, which can in turn be substituted by A1 such as above defined.
  • A is C1-C5 alkylene group.
  • the oxime derivative of formula II is advantageously prepared by the reaction of 6BIO with 1,2-dibromoethane in DMF and triethylamine Et 3 N at room temperature.
  • carbamate derivatives wherein R represents a CO—N(R2, R3) radical are prepared by the reaction of 6BIO with N,N-dialkylcarbamyl chloride.
  • the alcohols derivatives of formula I wherein A 1 is OH are prepared by the reaction of 6BIO with the appropriate 1,2-dibromoalcane or bromo alcohol. Indirubin and 6BIO were synthesized as previously reported 2 .
  • said derivatives are less cytotoxic than the parent 6BIO compound, and demonstrated potent GSK-3 inhibition in cellular models.
  • the invention thus provides means of great interest to treat pathologies associated with GSK3 deregulations such as Alzheimer's disease, diabetes, heart hypertrophy, in the field of embryonic stem cell pluripotency maintenance or the alteration of the circadian period in mammalians.
  • the invention thus relates to the new derivatives of formula I for use as drugs.
  • the invention then also concerns pharmaceutical compositions comprising therapeutically effective amount of at least one derivative of formula I or the pharmaceutically acceptable salts thereof, such as above defined, in association with a pharmaceutically acceptable vehicle.
  • the active ingredients, used in therapeutically effective amounts are mixed with the pharmaceutically acceptable vehicles for the mode of administration chosen.
  • These vehicles may be solids or liquids or gels.
  • the drugs may be under a form suitable for an administration preferably by intravenous route, but also by oral or injectable route intramuscular and subcutaneous routes, or nasal route.
  • the medicaments may be prepared in the form of gelatin capsules, tablets, sugar-coated tablets, capsules, pills and the like. Such medicaments may contain from 10 micrograms to 1 g of active ingredient per unit.
  • the medicaments are provided in the form of sterile or sterilizable solutions.
  • They may also be in the form of emulsions or suspensions.
  • the doses per dosage unit may vary for example from 1 micrograms to 1 g of active ingredient.
  • FIGS. 1 to 3 which represent, respectively:
  • FIGS. 1 a and 1 b the binding mode of analogues 11 (a) and 13 (b) to the binding pocket of GSK-3 ⁇ .
  • the piperazine substitution of both analogues interacts with asp200 and residues located at the phosphate sub-site of the binding pocket in addition to the hydrogen bonds (yellow dashed lines) formed between the indirubin scaffold and the receptor backbone
  • FIGS. 2 a and 2 b the inhibition of ⁇ -catenin phosphorylation at GSK-3 phosphorylation sites by the indirubin derivatives.
  • 2 a SH-SY5Y neuroblastoma cells were exposed for 6 hours to 10 ⁇ M of each indirubin, in the presence of a constant 2 ⁇ M level of the proteasome inhibitor MG132. The level of GSK-3-phosphorylated ⁇ -catenin was estimated by Western blotting following SDS-PAGE, using an antibody that specifically cross-reacts with GSK-3 phosphorylated ⁇ -catenin. Lack or reduction of the signal indicates that the indirubin has been able to inhibit GSK-3 within the neuroblastoma cells.
  • C control (DMSO); 6B, 6BIO; M6B, Methyl-6BIO (a control inactive analog of 6BIO); K, kenpaullone, a structurally unrelated GSK-3 inhibitor.
  • 2 b Dose-response curves for a selection of indirubins were run in an ELISA assay using the same antibodies directed against GSK-3 phosphorylated ⁇ -catenin. SH-SY5Y cells were exposed for 6 hours to a range of concentrations of each indirubin, in the presence of MG132, and extracts were assessed in the ELISA assay. Activity was expressed as percentage of phosphorylated ⁇ -catenin in untreated control cells.
  • FIGS. 3 a and 3 b the alteration of the circadian period in mammalian fibroblasts by the indirubin derivatives.
  • Rat-1 fibroblasts stably transfected with a P Per2 ::Fluc reporter construct show a robust circadian rhythm of luminescence as a gauge of clock-controlled Per2 promoter (P Per2 ) activity.
  • Cells were cultured up to 100% confluence and treated for 2 h with 0.1 ⁇ M dexamethasone to synchronize the oscillators. The medium was then replaced with assay medium supplemented with 0.1 mM luciferin and the luminescence rhythm was monitored for 4 days or more. Compounds were added to the culture dishes at 10 ⁇ M and left continuously.
  • DMSO DMSO was used as a solvent control. Regression analyses were used to determine period and phase of the luminescence rhythms.
  • 3 a Time-course of a typical luminescence rhythm recorded in control cells ( ⁇ ) or cells treated with indirubin 15 (•). White arrows indicate the peaks of luminescence in control cells, black arrows indicate the peaks of luminescence in indirubin 15 treated cells.
  • 3 b Period lengths calculated in cells exposed to various compounds.
  • C control
  • K kenpaullone.
  • Solubility Measurements Equilibrium solubilities were determined by adding an excess amount of solid to the medium (water, double distilled) followed by 5 min of sonification and overnight equilibration by stirring at ambient temperature (25 ⁇ 0.1° C.). The samples were centrifuged and aliquots were removed. Standard solutions were prepared for each compound in order to quantify the aforementioned saturated solutions, and reference curves were plotted for each compound. The absorbance of each saturated and standard solution was measured with a UV/vis spectrophotometer at wavelength that varied between 515 and 518 nm.
  • Kinase activities were assayed in buffer A (10 mM MgCl 2 , 1 mM EGTA, 1 mM DTT, 25 mM Tris-HCl pH 7.5, 50 ⁇ g heparin/ml) or C (homogenization buffer but 5 mM EGTA, no NaF and no protease inhibitors), at 30° C., at a final ATP concentration of 15 ⁇ M. Blank values were subtracted and activities calculated as pmoles of phosphate incorporated during a 30 mM incubation. The activities were expressed in % of the maximal activity, i.e. in the absence of inhibitors. Controls were performed with appropriate dilutions of dimethylsulfoxide. Phosphorylation of the substrate was assessed by the P81 phosphocellulose assay.
  • CDK1/cyclin B was extracted in homogenization buffer (60 mM ⁇ -glycerophosphate, 15 mM p-nitrophenylphosphate, 25 mM Mops (pH 7.2), 15 mM EGTA, 15 mM MgCl 2 , 1 mM DTT, 1 mM sodium vanadate, 1 mM NaF, 1 mM phenylphosphate, 10 ⁇ g leupeptin/ml, 10 ⁇ g aprotinin/ml, 10 ⁇ g soybean trypsin inhibitor/ml and 100 ⁇ M benzamidine) from M phase starfish ( Marthasterias glacialis ) oocytes and purified by affinity chromatography on p9 CKShs1 -sepharose beads, from which it was eluted by free p9 CKShs1 as previously described 4 .
  • homogenization buffer 60 mM ⁇ -glycerophosphate, 15 mM p-nitrophen
  • the kinase activity was assayed in buffer C, with 1 mg histone H1/ml, in the presence of 15 ⁇ M [ ⁇ - 33 P] ATP (3,000 Ci/mmol; 10 mCi/ml) in a final volume of 30 ⁇ l. After 30 min. incubation at 30° C., 25 ⁇ l aliquots of supernatant were spotted onto 2.5 ⁇ 3 cm pieces of Whatman P81 phosphocellulose paper, and, 20 sec. later, the filters were washed five times (for at least 5 min. each time) in a solution of 10 ml phosphoric acid/liter of water. The wet filters were counted in the presence of 1 ml ACS (Amersham) scintillation fluid.
  • CDK5/p25 was reconstituted by mixing equal amounts of recombinant human CDK5 and p25 expressed in E. coli as GST (Glutathione-S-transferase) fusion proteins and purified by affinity chromatography on glutathione-agarose (p25 is a truncated version of p35, the 35 kDa CDK5 activator). Its activity was assayed with histone H1 in buffer C as described for CDK1/cyclin B.
  • GST Glutathione-S-transferase
  • GSK-3 ⁇ / ⁇ was purified from porcine brain by affinity chromatography on immobilized axin 5 . It was assayed, following a 1/100 dilution in 1 mg BSA/ml 10 mM DTT, with 4 ⁇ M GS-1 (YRRAAVPPSPSLSRHSSPHQSpEDEEE), a GSK-3 specific substrate obtained from Millegen (Labege, France), in buffer A, in the presence of 15 ⁇ M [ ⁇ - 33 P] ATP (3,000 Ci/mmol; 10 mCi/ml) in a final volume of 30 ⁇ l. After 30 min. incubation at 30° C., 25 ⁇ l aliquots of supernatant were processed as described above.
  • SH-SY5Y human neuroblastoma cell line was grown at 37° C. with 5% CO 2 in DMEM supplemented with 2 mM L-glutamine (Invitrogen, Cergy Pontoise, France), plus antibiotics (penicillin-streptomycin) from Lonza, and a 10% volume of fetal calf serum (FCS) (Invitrogen). Drug treatments were performed on exponentially growing cultures at the indicated time and concentrations. Control experiments were carried also using appropriate dilutions of DMSO.
  • Cell viability was determined by means of the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H -tetrazolium) method after 48 hr of treatment as previously described 6 .
  • Rat-1 fibroblasts that have been stably transfected with a P Per2 ::Fluc reporter construct that shows a robust circadian rhythm of luminescence as a gauge of clock-controlled Per2 promoter (P Per2 ) activity ' .
  • the cells were cultured in DMEM (11965-092, GIBCO/Invitrogen) supplemented with 5% FBS, 50 units/ml penicillin, and 50 ⁇ g/ml streptomycin in a 5% CO 2 incubator at 37° C. Approximately 5 ⁇ 10 5 cells were seeded in a 35 mm dish at least 5 days before the experiment.
  • the cells were treated with 0.1 ⁇ M dexamethasone (Sigma) for 1 h to synchronize the oscillators among the cells in the population.
  • the medium was replaced with assay medium [DMEM without phenol red, supplemented with bicarbonate (350 mg/L), 5% FBS, 10 mM HEPES (pH 7.2), antibiotics (25 units/ml penicillin, 25 ⁇ g/ml streptomycin), and 0.1 mM luciferin (Promega)].
  • Culture dishes were sealed with a 40-mm microscope glass cover slip and high-vacuum grease to prevent the evaporation of culture medium.
  • the luminescence rhythm was monitored in a LumiCycle (Actimetrics Inc., Evanston, Ill., USA). Before being sealed, drugs were added to the culture dishes to different final concentrations and left continuously with the cells thereafter while the luminescence patterns were recorded for 5 days or more. DMSO was used as a solvent control. Regression analyses to determine period and phase of the luminescence rhythms were performed with the Chrono II program.
  • indirubins 1-26 The effects of indirubins 1-26 on three protein kinases and on the survival of human neuroblastoma SH-SY5Y cells are given in Table 2. Indirubins were tested at various concentrations on GSK-3 ⁇ / ⁇ , CDK1/cyclin B, CDK5/p25, as described in Experimental Section. IC 50 values, calculated from the dose-response curves, are reported in ⁇ M. The compounds were tested at various concentrations for their effects on SH-SY5Y cells survival after 48 h incubation as estimated using the MTS reduction assay. IC 50 values, calculated from the dose-response curves, are reported in ⁇ M.
  • the indirubin derivatives of the invention were tested for their effects on survival of SH-SY5Y neuroblastoma cells using an MTS reduction assay. These assays revealed that increased potency on GSK-3 was not associated with enhanced cell death (Table 1). Analogues 13, 14 and 15 (and their corresponding salts, 24, 25, 26) had little cell death inducing activities. The IC 50 values were respectively 28 ⁇ M, >100 ⁇ M, 94 ⁇ M (salts: 17 ⁇ M, >100 ⁇ M, 98 ⁇ M) to compare with the IC 50 of 6BIO, 9 ⁇ M).
  • substituted piperazine ring extension not only favours selectivity and efficacy towards GSK-3, allows better solubility, but also reduces their cytotoxicity. These features are particularly favorable for the use of these compounds in the study of GSK-3 in cellular systems, and also as potential therapeutic leads in the context of neurodegenerative diseases and diabetes.
  • GSK-3 is a key regulator of the circadian rhythm (aka the daily biological clock).
  • the circadian rhythm can be partially reproduced in a cellular system which is an excellent model system for circadian clocks in non-neural, peripheral tissues. This system was used to explore the possibility that GSK-3 inhibition could affect the circadian rhythm.
  • Rat-1 fibroblasts stably transfected with a P Per2 ::Fluc reporter construct show a robust circadian rhythm of luminescence as a gauge of clock-controlled Per2 promoter (P Per2 ).
  • Cells were cultured and treated first with 10 ⁇ M indirubin 15 as described in the Experimental section and their circadian rhythm of Per expression dependent luminescence was monitored during 4 days. A gradual shortening of the period length was clearly observed ( FIG. 3 a ).
  • FIG. 3 a Similar experiments were next performed with a small selection of indirubins and the period length was calculated as in FIG. 3 a .
  • the most efficient compounds in shortening the period length ( FIG. 3 b ) were also the most efficient at inhibiting ⁇ -catenin phosphorylation in the cellular assay ( FIG. 2 ), which supports the hypothesis that the action of the indirubins in shortening the circadian period is upon GSK-3.
  • Previous studies have suggested a key action of GSK-3 in regulating the circadian rhythms of mammalian cells using lithium as a pharmacological tool. Lithium lengthens the period of the circadian rhythm, whereas indirubins shorten the period ( FIG. 5 ).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US12/737,640 2008-08-01 2009-07-21 3′,6-substituted indirubins and their biological applications Expired - Fee Related US8829203B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/737,640 US8829203B2 (en) 2008-08-01 2009-07-21 3′,6-substituted indirubins and their biological applications

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US8543208P 2008-08-01 2008-08-01
EP08161646 2008-08-01
EP08161646A EP2149553B1 (de) 2008-08-01 2008-08-01 3',6-substituierte Indirubine und ihre biologischen Anwendungen
EP08161646.8 2008-08-01
PCT/IB2009/053153 WO2010013168A1 (en) 2008-08-01 2009-07-21 3',6-substituted indirubins and their biological applications
US12/737,640 US8829203B2 (en) 2008-08-01 2009-07-21 3′,6-substituted indirubins and their biological applications

Publications (2)

Publication Number Publication Date
US20110136808A1 US20110136808A1 (en) 2011-06-09
US8829203B2 true US8829203B2 (en) 2014-09-09

Family

ID=40225521

Family Applications (1)

Application Number Title Priority Date Filing Date
US12/737,640 Expired - Fee Related US8829203B2 (en) 2008-08-01 2009-07-21 3′,6-substituted indirubins and their biological applications

Country Status (6)

Country Link
US (1) US8829203B2 (de)
EP (2) EP2149553B1 (de)
JP (1) JP5577336B2 (de)
AT (2) ATE529402T1 (de)
CA (1) CA2732232C (de)
WO (1) WO2010013168A1 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022229986A1 (en) * 2021-04-29 2022-11-03 Jawaharlal Nehru Centre For Advanced Scientific Research Indirubin compounds and methods thereof

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5448455B2 (ja) * 2005-12-23 2014-03-19 サーントゥル ナシオナル ドゥ ラ ルシェルシュ シャーンティフィク （セ エン エール エス） 新規３’−，７−置換インジルビンおよびそれらの適用
EP2149553B1 (de) 2008-08-01 2011-10-19 Centre National de la Recherche Scientifique 3',6-substituierte Indirubine und ihre biologischen Anwendungen
WO2011003988A1 (en) 2009-07-08 2011-01-13 INSERM (Institut National de la Santé et de la Recherche Médicale) A method for inducing extended self-renewal of functionally differentiated somatic cells
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
TW201215387A (en) 2010-07-05 2012-04-16 Sanofi Aventis Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
TW201215388A (en) 2010-07-05 2012-04-16 Sanofi Sa (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
TW201221505A (en) 2010-07-05 2012-06-01 Sanofi Sa Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament
WO2013011841A1 (ja) * 2011-07-15 2013-01-24 学校法人日本大学 悪性腫瘍に対する高選択的細胞毒性を有するインディルビン誘導体
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
US9512076B2 (en) 2012-02-03 2016-12-06 City Of Hope Indirubin derivatives and uses thereof in treating chronic myelogenous leukemia
US10435367B2 (en) * 2013-03-14 2019-10-08 City Of Hope Indirubin derivatives, and uses thereof
CA2868302A1 (en) 2012-03-23 2013-09-26 Dennis M. Brown Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
CA2902914A1 (en) * 2013-03-14 2014-09-25 City Of Hope 5-bromo-indirubins
US20150259288A1 (en) 2014-03-14 2015-09-17 City Of Hope 5-bromo-indirubins
RU2763346C2 (ru) * 2017-10-31 2021-12-28 Пелемед Ко., Лтд. Фармацевтическая композиция для предупреждения или лечения острого миелоидного лейкоза или метастатического рака молочной железы
US12303490B2 (en) 2019-11-04 2025-05-20 Ck Regeon Inc. Compositions and methods for suppressing and/or treating neurodegenerative diseases and/or a clinical condition thereof
CN113072540B (zh) * 2021-03-29 2023-07-14 贵州医科大学 一种靛玉红衍生的降解剂及其制备与应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005041954A1 (en) 2003-10-28 2005-05-12 The Rockefeller University Indirubin-type compounds, compositions, and methods for their use
US6987092B1 (en) 1999-04-12 2006-01-17 Faustus Forschungs Cie. Translational Cancer Research Gmbh Indigoid bisindole derivatives
US20100331327A1 (en) 2005-12-23 2010-12-30 Centre National De La Recherche Scientifique (Cnrs) 7-substituted indirubin-3'oximes and their applications
US20110136808A1 (en) 2008-08-01 2011-06-09 Laurent Meijer 3',6-substituted indirubins and their biological applications

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6987092B1 (en) 1999-04-12 2006-01-17 Faustus Forschungs Cie. Translational Cancer Research Gmbh Indigoid bisindole derivatives
WO2005041954A1 (en) 2003-10-28 2005-05-12 The Rockefeller University Indirubin-type compounds, compositions, and methods for their use
US20070276025A1 (en) 2003-10-28 2007-11-29 Laurent Meijer Indirubin-Type Compounds, Compositions, and Methods for Their Use
US20100331327A1 (en) 2005-12-23 2010-12-30 Centre National De La Recherche Scientifique (Cnrs) 7-substituted indirubin-3'oximes and their applications
US20110136808A1 (en) 2008-08-01 2011-06-09 Laurent Meijer 3',6-substituted indirubins and their biological applications

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Cecil Textbook of Medicine, 20th edition (1996), vol. 2, pp. 1992-1996. *
Cecil Textbook of Medicine, 20th edition (1996), vol. 2, pp. 2050-2057. *
FDA mulls drug to slow late-stage Alzheimer's [online], [retrieved on Sep. 23, 2003]. Retrieved from the Internet, URL; http://www.cnn.com/2003/HEALTH/conditions/O9/24/alzheimers.drug.ap/indexhtml>. *
Ferandin et al., "3′-Substituted 7-Halogenoindirubins, a New Class of Cell Death Inducing Agents", Journal of Medicinal Chemistry, vol. 49, No. 15, 2006, pp. 4638-4649, XP002453471.
Ferandin et al., "3'-Substituted 7-Halogenoindirubins, a New Class of Cell Death Inducing Agents", Journal of Medicinal Chemistry, vol. 49, No. 15, 2006, pp. 4638-4649, XP002453471.
Ferandin, et al. Document No. 145:271522 (2006), retrieved from CAPLUS. *
International Search Report for PCT/IB2006/004152, mailed Oct. 23, 2007.
International Search Report for PCT/IB2009/053153, mailed Sep. 24, 2009.
K. Vougogiannopoulou et al., "Soluble 3', 6-substituted Indirubins with Enchanced Selectivity towards Glycogen Synthase Kinase-3 Alter Circadian Period", J. Med. Chem., vol. 51, No. 20, Sep. 25, 2008, pp. 6421-6431.
K. Vougogiannopoulou et al., "Soluble 3′, 6-substituted Indirubins with Enchanced Selectivity towards Glycogen Synthase Kinase-3 Alter Circadian Period", J. Med. Chem., vol. 51, No. 20, Sep. 25, 2008, pp. 6421-6431.
Meijer et al., "GSK-3-Selective inhibitors derived from Tyrian Purple Indirubins", Chemistry & Biology, vol. 10, 2003, pp. 1255-1266, XP002453469.
Olivier, et al. Document No. 150:162202 (2008), retrieved from CAPLUS. *
Polychronopoulos et al., "Structural bases for the synthesis of Indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin dependent kinases", Journal of Medicinal Chemistry, vol. 47, 2004, pp. 935-946, XP002453468.
Ribas et al, "7-Bromindirubin-3′-oxime induces capase-independent cell death", Oncogene, vol. 25, No. 47, 2006, pp. 6304-6318, XP002453470.
Ribas et al, "7-Bromindirubin-3'-oxime induces capase-independent cell death", Oncogene, vol. 25, No. 47, 2006, pp. 6304-6318, XP002453470.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022229986A1 (en) * 2021-04-29 2022-11-03 Jawaharlal Nehru Centre For Advanced Scientific Research Indirubin compounds and methods thereof

Also Published As

Publication number Publication date
JP5577336B2 (ja) 2014-08-20
JP2011529873A (ja) 2011-12-15
US20110136808A1 (en) 2011-06-09
EP2328866A1 (de) 2011-06-08
CA2732232A1 (en) 2010-02-04
EP2328866B1 (de) 2012-02-29
ATE529402T1 (de) 2011-11-15
EP2149553B1 (de) 2011-10-19
EP2149553A1 (de) 2010-02-03
ATE547401T1 (de) 2012-03-15
CA2732232C (en) 2017-11-07
WO2010013168A1 (en) 2010-02-04

Similar Documents

Publication Publication Date Title
US8829203B2 (en) 3′,6-substituted indirubins and their biological applications
US12564583B2 (en) Small molecules against cereblon to enhance effector T cell function
Vougogiannopoulou et al. Soluble 3′, 6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase-3 alter circadian period
ES2297724T3 (es) Nuevas 2-bencilaminodihidropteridinonas, procedimiento para su obtencion y su empleo como medicamentos.
AU2007334379B2 (en) Compounds useful as protein kinase inhibitors
KR0174752B1 (ko) 이환식 헤테로환 함유 술폰아미드 유도체 및 그 제조방법
ES2267873T3 (es) Derivados de 4-aminotiazol, su preparacion y uso como inhibidores de kinasas dependientes de ciclina.
US20140243324A1 (en) Use of hematopoietic growth factor mimetics
US7071217B2 (en) Substituted oxindole derivatives as tyrosine kinase inhibitors
US6747046B2 (en) Substituted N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives, their production and use as pharmaceutical agents
US7781477B2 (en) Therapeutic use of N-(1H-Indolyl)-1H-indole-2-carboxamide derivatives
EP3891137B1 (de) Kleinmolekülige ire1-inhibitoren
MX2013006462A (es) Pirazolopirimidinas sustituidas como activadores de glucocerebrosidasa.
US6169106B1 (en) Indolinones having kinase inhibitory activity
CN116897153A (zh) 一种三氮唑类衍生物及其制备方法和应用
CN115873065A (zh) 半胱氨酸蛋白酶抑制剂及其用途
CN108929312A (zh) 具有cdk或hdac抑制活性的新型苯并杂环联嘧啶抑制剂
CA3173733A1 (en) Small molecule inhibitors of scl15a4 with anti-inflammatory activity
CN114957250B (zh) N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用
JP2006504631A (ja) 脳虚血障害又はｃｎｓ障害の処置のための薬剤としてのピペラジンベンゾチアゾール
US7964629B2 (en) Inhibitors of isoprenylcysteine carboxyl methyltransferase
EA014236B1 (ru) Новые пиперазиновые производные диалкилоксиндолов
JP2007500167A (ja) インドール−７−スルホンアミド誘導体、それらの調製、および５−ｈｔ−６調節剤としてのそれらの使用
US20240246942A1 (en) Kinase inhibitors for the treatment of neurodegenerative diseases

Legal Events

Date Code Title Description
AS Assignment

Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MEIJER, LAURENT;SKALTSOUNIS, LEANDROS;MIKROS, EMMANUEL;AND OTHERS;SIGNING DATES FROM 20110303 TO 20111123;REEL/FRAME:027365/0286

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551)

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20220909

AS Assignment

Owner name: NIH-DEITR, MARYLAND

Free format text: CONFIRMATORY LICENSE;ASSIGNOR:VANDERBILT UNIVERSITY;REEL/FRAME:063704/0542

Effective date: 20230515